Synthesis of trans-fused Octahydroisoindole-1-carboxylic Acids

Abstract

trans-Fused octahydroisoindole-1-carboxylic acids are bicyclic proline analogues of potential interest in the search for new drugs. Within this work, the trans-fused octahydroisoindole system has been constructed using methyl trans-2-(hydroxymethyl)cyclohexane-1-carboxylate as the key synthetic precursor, in turn readily prepared from inexpensive cis-cyclohexane-1,2-dicarboxylic anhydride. Both the (1S*,3aR*,7aR*)- and the (1R*,3aR*,7aR*)-octahydroisoindole-1-carboxylic acids were prepared through the Strecker reaction of methyl trans-2-formylcyclohexane-1-carboxylate as the key step. Finally, (1S*,3aR*,7aR*)-octahydroisoindole-1-carboxylic acid was obtained with good yields in a highly stereoselective manner using (3aR*,7aR*)-octahydroisoindole-1-one as a suitable scaffold. Keywords: Amino acids, proline analogues, strecker, trans-fused ring systems, diastereoselectivity, lactamization.